Many modified antisense oligos are being tested in clinical trials with fomivirsen (Vitravene; Isis) as the first oligo drug approved by the U.S. FDA for the treatment of eye cytomegalovirus infection. Currently, such chemical modifications are also being applied to synthetic siRNAs, and some modified siRNAs have been reported to be more potent and stable than their native siRNAs. In the synthesis and incorporation of isonucleosides into antisense oligos, we found that modified antisense oligos not only possess strong nuclease resistance but more interestingly become good substrates of RNase H. An introduction of an amino group into the isonucleoside may increase the thermal stability of the isonucleoside-modified oligonucleotide with its complementary sequence. The chemical synthesis and incorporation of D- and L-isonucleosides into the siRNA duplex and analyze the effect of such a modification at different positions on siRNA structural stability and functional activity will be discussed.

Chemical modified antisense oligonucleotide and siRNA

243rd National Meeting (2012)

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